Pentoxifylline as a rescue treatment for DMD

Abstract

Objective: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). Methods:This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (ϳ20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test.Results: A total of 64 boys with DMD with a mean age of 9.9 Ϯ 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p ϭ 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. Conclusion:The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. Classification of evidence:This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

“…Thus, its efficacy in these subjects could not be assessed, and alternative routes of administration have been investigated. In a 12-month double-blind study of 64 DMD boys, treatment with a slow-release pentoxifylline formulation was better tolerated, but did not improve or halt the deterioration of muscle strength and function 200 .…”

Immune-mediated pathology in Duchenne muscular dystrophy

“…This agent does not appear to exert anti-fibrotic effects through modulation of TGF-β, but instead is thought to counteract nitric oxide synthase deficiency at the myofiber membrane and improve blood flow. Pentoxifylline, a nonselective phosphodiesterase inhibitor with both anti-inflammatory and antifibrotic activities (thought to act through modulation of TGF-β signaling) (106), nonetheless failed to prevent deterioration in muscle function over a 1-year evaluation period in DMD patients (Table 1) (107). Pirfenidone, an antifibrotic agent (108) that has been shown to inhibit the secretion of TNF-α and TGF-β and to inhibit TGF-β signaling by preventing nuclear accumulation of active Smad2/3 complexes in animal studies (109), is approved in Europe and the United States for idiopathic pulmonary fibrosis (Table 1).…”

Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy

“…Despite the results, the investigators point out that the PTX treatment group showed a trend toward slower rate of decline and raise the possibility that a longer study may identify a beneficial, synergistic role for PTX. They also emphasize that future studies need to evaluate higher doses of PTX since doses of 120 mg/kg were necessary to attenuate the upregulation of TGF beta pathways in nonhuman primates and the negative results in the current study evaluated a dose of 20 mg/kg [56].…”

“…Pentoxifylline (PTX) is a phosphodiesterase inhibitor that has recently undergone Phase II clinical trial assessment [56]. In preclinical studies, PTX treatment slowed muscle strength deterioration by 51% in exercised mdx mice [57].…”

“…In preclinical studies, PTX treatment slowed muscle strength deterioration by 51% in exercised mdx mice [57]. However, a recent multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX to placebo in corticosteroid-treated boys with moderate to late ambulatory stage DMD (age 7 and older) failed to show improvement or slow the decline in overall muscle strength and function [56]. Despite the results, the investigators point out that the PTX treatment group showed a trend toward slower rate of decline and raise the possibility that a longer study may identify a beneficial, synergistic role for PTX.…”